The present invention relates generally to synthetic organic chemistry, and particularly to a process for adding aldehydes to certain organic compounds having active C--H bonds.
Base-catalyzed reaction of aldehydes or ketones with compounds having active methylene groups is a widely employed reaction commonly known as the Knoevenagel condensation. Activation of the methylene group is brought about by attachment of a group such as nitro, cyano, or acyl. In most cases, two such groups are required to provide sufficient activation. The primary product is typically an unsaturated compound resulting from combination of starting materials, followed by dehydration. The primary product can undergo a Michael addition reaction with a second molecule of the active methylene compound to provide a bis compound. Variations of the Knoevenagel condensation are discussed by Jones, "The Knoevenagel Condensation", in Cope et al., eds., Organic Reactions Vol. 15, pp. 204-273, (Wiley, New York, 1967).
A special case of the Knoevenagel reaction is the Henry addition, which involves base-catalyzed combination of an aldehyde or ketone and a nitroalkane. This reaction is discussed by Baer et al., "Activating and Directing Effects of the Nitro Group in Aliphatic Systems", in Feuer et al., eds., The Chemistry of the Nitro and Nitroso Groups, pp. 75-187, (Wiley-Interscience, New York, 1970).
A number of workers have disclosed aldol condensations of aldehydes and ketones catalyzed by transition metal complexes. As used herein, "condensation" refers to a reaction wherein addition is followed by dehydration.
Iwata et al., Bull. Chem. Soc. Jpn. 49:1369 (1976), disclose aldol condensations of aromatic and aliphatic aldehydes with ketones in the presence of Cu(II) ion.
Irie et al., Bull. Chem. Soc. Jpn. 53:1366 (1980), disclose aldol condensations of aldehydes with ketones, catalyzed by transition metal(II) complexes, to provide .alpha.,.beta.-unsaturated ketones. Specifically, Irie et al. report use of complexes of Co(II), Ni(II), Cu(II), and Zn(II) acetates with 2,2'-bipyridine as catalysts in these reactions, which were conducted at 80.degree. C. in dimethylformamide.
Irie et al., Bull. Chem. Soc. Jpn. 54:1195 (1981), describe condensations of benzaldehyde with acetophenone, using a Co(II) acetate-2,2'-bipyridine catalyst complex in dimethylformamide.
Watanabe et al., Bull. Chem. Soc. Jpn. 55:3208 (1982), disclose aldol condensation reactions catalyzed by Co(II) complexes of pyridine-containing copolymers. Watanabe et al. note that use of dimethylformamide or dimethyl sulfoxide as solvent is required in these reactions, and that condensations involving aliphatic aldehydes and ketones did not proceed as successfully as those involving aromatic compounds.
Irie, Nippon Kagaku Kaishi 1983(1):150 (1983) (CA 98:160318m), describes addition of certain aromatic aldehydes to nitromethane in the presence of a Ni(II)-2,2'-bipyridine complex to provide aromatic nitroalcohols. In this case, addition was not followed by dehydration. Dimethylformamide was employed as solvent.
It has now been found that addition of aldehydes to compounds having active C--H bonds can be efficiently catalyzed under neutral conditions by electron-rich, low valent transition metal complexes containing small cone angle phosphine or arsine ligands. This reaction provides alcohols in high yields, primarily without continuation to provide dehydration products. In addition, the reaction of the present invention is quite sensitive to catalyst steric hindrance, enabling avoidance of further combination of initial products with aldehyde starting materials. The reaction provided herein can be conducted with equimolar quantities of reactants, and is not limited to particular solvent systems.